HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation
HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation
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DOI：
10.1016/j.virol.2007.10.042
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发表时间：
2008-03-30
期刊：
影响因子：
3.7
通讯作者：
Pitha, Paula M.
中科院分区：
文献类型：
--
作者：
Okumura, Atsushi;Alce, Tim;Pitha, Paula M.
在病毒感染的早期阶段IRF-3的活化对于启动抗病毒应答至关重要;然而，尚未表征HIV-1感染细胞中IRF-3的活化。我们证明，HIV-1感染的早期步骤不会导致IRF-3的激活和核转位;相反，由于泛素相关的蛋白体降解，IRF-3蛋白的相对水平降低。解决这种效应的分子机制，我们表明，降解是独立的HIV-1复制和病毒体相关的辅助蛋白Vif和Vpr可以独立地降解IRF-3。这两个基因的无效突变降低了HIV-1病毒下调IRF-3水平的能力。降解与Vif和Vpr介导的IRF-3泛素化相关，并且独立于IRF-3的活化。N-末端赖氨酸残基被证明在Vif和Vpr介导的IRF-3降解中发挥关键作用。这些数据暗示Vif和Vpr在最初的抗病毒反应的破坏，并指出需要HIV-1在复制的非常早期阶段规避抗病毒反应。(C)2007年爱思唯尔公司All rights reserved.
The activation of IRF-3 during the early stages of viral infection is critical for the initiation of the antiviral response; however the activation of IRF-3 in HIV-1 infected cells has not yet been characterized. We demonstrate that the early steps of HIV-1 infection do not lead to the activation and nuclear translocation of IRF-3; instead, the relative levels of IRF-3 protein are decreased due to the ubiquitin-associated proteosome degradation. Addressing the molecular mechanism of this effect we show that the degradation is independent of HIV-1 replication and that virion-associated accessory proteins Vif and Vpr can independently degrade IRF-3. The null mutation of these two genes reduced the capacity of the HIV-1 virus to down modulate IRF-3 levels. The degradation was associated with Vif- and Vpr-mediated ubiquitination of IRF-3 and was independent of the activation of IRF-3. N-terminal lysine residues were shown to play a critical role in the Vif- and Vpr-mediated degradation of IRF-3. These data implicate Vif and Vpr in the disruption of the initial antiviral response and point to the need of HIV-1 to circumvent the antiviral response during the very early phase of replication. (C) 2007 Elsevier Inc. All rights reserved.